The present invention relates to a hitherto unknown class of compounds comprising new matrix metalloproteinase inhibitors, which are 1,3,2-oxazaphos-phacycloalkane based hydroxamic acids, carboxylic acids, phosphonic acids or thiols, to pharmaceutical compositions containing said compounds, to methods of treating patients with said compounds, and to the use of such compounds in the preparation of medicine. In particular, the compounds are inhibitors of matrix metalloproteinases involved in tissue degradation. Some of the compounds of the invention are, in addition, inhibitors of the release of tumour necrosis factor-xcex1 (TNF-xcex1) from cells.
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which exhibit proteolytic activity towards most if not all of the constituents of the extra-cellular matrix, such as the interstitial and basement membrane collagens, fibro-nectin, and laminin. They play a key role in both physiological and pathological tissue degradation.
At least 17 different and yet highly homologous MMP-species have been characterised. They share a catalytic domain with the VAAHEXGHXXGXXH motif responsible for ligating zinc, which is essential for the catalytic function. MMP family members differ from each other structurally by the presence or absence of additional domains that contribute to activities, such as substrate specificity, inhibitor binding, matrix binding and cell-surface localisation. [H. Birkedal-Hansen, W. G. Moore, M. K. Bodden, C. J. Windsor, B. Birkedal-Hansen, A. DeCarlo: Crit. Rev. Oral Biol. Med. (1993) 4, 197-250 and A. F. Chambers, L. M. Matristan: J. Natl. Cancer Inst. (1997) 89(17), 1260-1270]. There are three major groups of MMPs, identified by their substrate preferences: collagenases degrade fibrillar collagen, stromelysins prefer proteoglycans and glycoproteins as substrates and gelatinases are particularly potent in degradation of nonfibrillar and denatured collagens (gelatine).
MMPs are also believed to be important in the processing, or secretion, of biologically important cell mediators, such as TNF-xcex1, and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD 23 (for a more complete list see N. M. Hooper et al.: Biochem. J. (1997) 321, 265-279).
Potential therapeutic indications of MMP inhibitors have been discussed in the literature [e.g. T. H. Vu, Z. Werb. (1998) (In: Matrix Metalloproteinases. 1998. Edited by W. C. Parks and R. P. Mecham. Pp115-148. Academic Press. ISBN 0-12-545090-7); D. E. Mullins et al.: Biochem. Biophys. Acta (1983) 695, 117-214; B. Henderson et al.: Drugs of the Future (1990) 15, 495-508; R. Reich et al.: Cancer Res. (1988) 48, 3307-3312]. Compounds which have the property of inhibiting the action of matrix metalloproteinases are thought to be potentially useful for, but not restricted to, the treatment or prophylaxis of conditions involving tissue breakdown and inflammation, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, skin ageing and tumour metastasis, tumour invasion and tumour growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angio fibromas and hemangiomas. However, the relative contributions of individual MMPs in any of the above disease states is not yet fully understood.
TNF-xcex1 is a cytokine which is produced as a 28-kDa precursor and released in an active 17-kDa form. This active form can mediate a large number of deleterious effects in vivo, including inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration of TNF-xcex1 can cause cachexia and anorexia; accumulation of excess TNF-xcex1 can be fatal. Compounds which inhibit the production or action of TNF-xcex1 are therefore thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological and malignant diseases. These include, but are not limited to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, Crohn""s disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, cancer, rheumatoid arthritis and multiple sclerosis.
TNF-xcex1 convertase is a metalloprotease involved in the biosynthesis of TNF-xcex1. Inhibition of TNF-xcex1 convertase inhibits production of TNF-xcex1. Since excessive TNF-xcex1 production has been noted in several disease conditions characterised by MMP-mediated tissue degradation, including multiple sclerosis, arthritis and cancer, compounds which inhibit both MMPs and TNF-xcex1 production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage sites in the natural substrates of the MMPs. Other known MMP inhibitors are less peptidic in structure, and may be viewed as pseudopeptides or peptidomimetics, e.g. sulfonamides. Such compounds usually have a zinc binding group, which most often is a hydroxamic acid, reverse hydroxamic acid, carboxylic acid, sulphhydryl, and oxygenated phosphorous (e.g. phosphinic acid and phosphonamides including aminophosphonic acid) groups.
Although numerous MMP inhibitors with potent in vitro activities are known, many have not been suitable for further development as medicines, since they have lacked any useful activity when administered orally at pharmaceutically acceptably doses. Although it is known that a number of factors influence oral bioavailability, the design of enzyme inhibitors with high oral bioavailability is far from straightforward. Finding a series of compounds that permits a good balance of intrinsic level of activity, water solubility, oral absorption, and favourable pharmacokinetic properties is a continuing problem in the art, since those properties can vary in an unpredictable way in relation to the structure. Identifying MMP inhibitors having such properties remains a challenge.
Prior art has consisted of simple peptidic compounds as well as linear and cyclic sulfonamide compounds, e.g. EP-A-0489577, WO 96/16931, WO 96/33991, WO 97/44315 and WO 00/09485. Only a single example of a prior art patent publication exists depicting simple linear phosphinamide compounds [WO 98/08853]. These are structurally diverse from the cyclic compounds of general formula (I). Prior art has depicted only 1,3,2-oxazaphosphorocycloalkanes with simple phenyl and alkyl substituents, however they do not contain the requisite hydroxamic acid or other zinc binding groups (e.g. PL 149593, FR 2567129, Izv. Akad. Nauk., Ser. Khim (1995) (11), 2241-9). It has now surprisingly been found that the novel 1,3,2-oxazaphoshacycloalkane based compounds of general formula (I) of the present invention are potent MMP inhibitors. Preferred compounds of the present invention display nanomolar to micromolar potency in inhibiting MMPs, such as MMP-13, MMP-9 and MMP-3.
The present invention relates to a novel class of compounds of the general formula I 
wherein Y is O or S;
n is 1, 2, 3 or 4;
X represents hydroxamic acid, carboxylic acid, phosphonic acid, acetylthiomethyl group or a mercaptomethyl group;
R1 is 
wherein E, when present represents, a bond or optionally substituted methylene or ethylene;
s and t are independently 0, 1, 2 or 3;
A and Axe2x80x2 independently represent a bond, or a saturated or unsaturated, optionally substituted cyclic or heterocyclic hydrocarbon di- or triradical;
Z represents a bond, O, S, C(O), C(O)NR7, NR7C(O) or NR7, wherein R7 is hydrogen, hydroxy, branched or straight, saturated or unsaturated, optionally substituted hydrocarbon radical;
R5 represents a bond, alkane or alkene diradical, one or more ether diradicals (Rxe2x80x94Oxe2x80x94Rxe2x80x2) or amine diradicals (Rxe2x80x94Nxe2x80x94Rxe2x80x2), wherein R and Rxe2x80x2 independently represent alkane or alkene diradicals with a C-content from 0 to 3;
R6 represents hydrogen, hydroxy, halogen, cyano, nitro, branched or straight, saturated or unsaturated, optionally substituted hydrocarbon radical, unsaturated optionally substituted cyclic or heterocyclic hydrocarbon radical, NR8R9, C(O)NR8R9, C(O)R8, CO(O)R8, S(O)2R9, wherein each R8 and R9 independently represent hydrogen, halogen, a branched or straight, saturated or unsaturated, optionally substituted hydrocarbon radical;
R2 represents hydrogen, (C1-8)alkyl, (C2-6)alkenyl, (C3-8)cycloalkyl, aryl(C0-6)alkyl or heteroaryl(C0-6)alkyl;
provided that if A, Axe2x80x2, Z and R5 are all bonds, and s and t are both 0 (zero), then R6 is different from hydrogen;
or a salt, hydrate or solvate thereof.
As used in the specification, unless specified to the contrary, the following terms have the meaning indicated:
xe2x80x9cAlkylxe2x80x9d refers to a straight or branched chain alkyl moiety, consisting solely of carbon and hydrogen, containing no unsaturation and having the number of carbon atoms specified, including for example methyl, n-propyl, isobutyl, t-butyl, hexyl and dodecyl.
xe2x80x9c(C2-C6)alkenylxe2x80x9d refers to a straight or branched chain alkenyl moiety having 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. This term would include, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
The term xe2x80x9calkoxyxe2x80x9d is intended to indicate a radical of formula OR, wherein R is alkyl as defined above, e.g. methoxy, ethoxy, propoxy, butoxy, etc.
The term xe2x80x9calkoxycarbonylxe2x80x9d is intended to indicate a radical of formula xe2x80x94COOR wherein R is alkyl as defined above, e.g. methoxycarbonyl, ethoxycabonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc.
The term xe2x80x9csaturated cyclic hydrocarbonxe2x80x9d is intended to indicate cyclic compounds, optionally fused bicyclic rings, containing hydrogen and carbon, which are saturated, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane and decaline.
The term xe2x80x9cunsaturated cyclic hydrocarbonxe2x80x9d is intended to indicate cyclic compounds, optionally fused bicyclic rings, containing hydrogen and carbon, in which one or more carbon-carbon bond is unsaturated, such as cyclopentene, cyclohexene, cyclohexadiene, cycloheptene, benzene, naphtene and 1,4-dihydronaphtene, indane and indene.
The term xe2x80x9cheterocyclic hydrocarbonxe2x80x9d is intended to indicate saturated or unsaturated cyclic compounds of hydrogen, carbon, and one or more heteroatoms selected from O, S, N and P, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrrolidine, pyridine, pyrimidine, tetrahydrotiophene, tetrahydrofuran, piperidine, piperazine, phosphalane, phosphorinane and phosporepane.
xe2x80x9cArylxe2x80x9d refers to phenyl or naphtyl.
xe2x80x9cCycloalkylxe2x80x9d means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclopentyl, cyclohexyl, and cyclooctyl.
xe2x80x9cHeteroarylxe2x80x9d refers to pyridyl, indolyl, thienyl or imidazolyl.
Unless otherwise specified in the context in which it occurs, the term xe2x80x9csubstitutedxe2x80x9d as applied to any moiety herein means substituted with up to four substituents, each of which independently may be a (C1-6)alkoxy, (C1-6)alkyl, phenyl, hydroxy, thio, (C1-6)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), cyano, cyanomethyl, trifluoromethyl, nitro, carboxy, xe2x80x94CONH2, haloalkyl, alkylamino, hydroxyalkyl, alkylcarbonyl, xe2x80x94CONHR12 or xe2x80x94CONR12R12 wherein R12 is a (C1-C6)alkyl group or the residue of a natural xcex1-amino acid.
Salts of the compounds of the invention can be formed with bases. Such salts include salts derived from inorganic or organic bases, for example metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
If the compounds of the invention contain basic moieties, salts may also be formed with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic, and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, succinic acid, benzoic acid, maleic acid, these examples being considered as non-limiting for the invention.
There are chiral centres in the compounds according to the invention due to the presence of an asymmetric carbon atom and an asymmetric phosphorous atom. The presence of several chiral centres gives rise to a number of diastereoisomers with R or S stereochemistry at each chiral centre. Likewise, the occurrence of carbon-carbon double bonds and ringsystems gives rise to the presence of geometric and stereo isomeric forms. General formula (I), and (unless specified otherwise) all other formulae in this specification are to be understood to include all such isomers, in pure form, or as mixtures thereof.
In the compounds of the invention, the preferred stereochemistry is in general as follows:
C atom carrying the R2 group xe2x80x94(R), but mixtures in which the above configurations predominate are also contemplated. Without limiting the generality of the foregoing:
Preferred compounds of formula (I) are those in which X represents CONHOH. More preferred compounds of formula (I) are those in which X represents CONHOH, n=1 or 2 and Y represents oxygen.
In a preferred embodiment, R1 is selected from the group consisting of alkoxyphenyl, phenoxyphenyl optionally substituted with halogen, halogen substituted hydrocarbon radical or cyano, phenylalkyl or naphtylalkyl both optionally substituted with halogen, phenyl optionally substituted with halogen or nitro, hydrocarbon radical, biphenyl optionally substituted with halogen, benzylphenoxyl, phenylxe2x80x94(NH)xe2x80x94C(O)xe2x80x94phenyl optionally substituted with halogen or cyano and methoxy.
Examples of particular R1 groups include 4-methoxyphenyl, 4-(4-chlorophenoxy)-phenyl, 4-(4-bromophenoxy)-phenyl, 4-(4-trifluoromethylphenoxy)-phenyl, 4xe2x80x2bromo-4-biphenylyl, N-(4-chlorbenzoyl)-4-aminophenyl, 4-nitrophenyl, N-benzoyl-4-aminophenyl, 4-phenoxyphenyl.
In a preferred embodiment, R2 is selected from the group consisting of hydrogen, (C1-8)alkyl, (C2-6)alkenyl and aryl(C0-6)alkyl.
Examples of particular R2 groups include hydrogen, isopropyl, allyl, isobutyl, n-butyl, n-octyl and benzyl.
Examples of the invention are:
(xc2x1)-2-(4-Chlorophenoxy)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Chlorophenoxy)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-[(4-Bromophenyl)methyl]-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-[(4-Biphenylyl)methyl]-2-oxo- 1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Biphenylyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Biphenylyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-Heptyl-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic
(xc2x1)-2-Heptyl-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-[4-(phenylamino)phenyl]-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-phenyl-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-phenyl-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-phenyl-1,3,2-oxazaphosphoronane-3-acetohydroxamic acid
(xc2x1)-xcex1-Butyl-2-oxo-2-phenyl-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-xcex1-Butyl-2-oxo-2-phenyl-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Methoxyphenyl)-2-oxo-1,3,2-oxazaphosphoronane-3-acetohydroxamic acid.
(xcex1R) -2-(4- Methoxyphenyl)-xcex1-(1-methylethyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1).
(xcex1R)-2-(4-Methoxyphenyl)-xcex1-(1-methylethyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xc2x1)-xcex1-Butyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-xcex1-Butyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 2).
(xc2x1)-xcex1-Butyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-xcex1-Butyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 2).
(xc2x1)-xcex1-Butyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-xcex1-Butyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid (diastereomers 2).
(xc2x1)-xcex1-Allyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-xcex1-Allyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 2,).
(xc2x1)-xcex1-Allyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 1,).
(xc2x1)-xcex1-Allyl-2-(4-methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 2).
(xcex1R)-2-(4-Methoxyphenyl)-xcex1-(2-methylpropyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1, compound 130).
(xcex1R)-2-(4-Methoxyphenyl)-xcex1-(2-methylpropyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xcex1S)-2-(4-Methoxyphenyl)-xcex1-(2-methylpropyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1).
(xcex1S)-2-(4-Methoxyphenyl)-xcex1-(2-methylpropyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xc2x1)-2-(4-Methoxyphenyl)-xcex1-(2-methylpropyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-2-(4-Methoxyphenyl)-xcex1-(2-methylpropyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 2).
(xc2x1)-2-(4-Methoxyphenyl)-xcex1-propyl-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-2-(4-Methoxyphenyl)-xcex1-propyl-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 2,).
(xc2x1)-2-(4-Methoxyphenyl)-xcex1-octyl-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-2-(4-Methoxyphenyl)-xcex1-octyl-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 2,).
(xcex1R)-2-(4-Methoxyphenyl)-2-oxo-xcex1-phenylmethyl-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1).
(xcex1S)-2-(4-Methoxyphenyl)-2-oxo-xcex1-phenylmethyl-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1).
(xcex1S)-2-(4-Methoxyphenyl)-2-oxo-xcex1-phenylmethyl-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xc2x1)-2-Oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid.
(xc2x1)-xcex1-Allyl-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 1.).
(xc2x1)-xcex1-Allyl-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomers 2).
(xcex1R)-xcex1-(2-Methylpropyl)-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1).
(xcex1R)-xcex1-(2-Methylpropyl)-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xcex1R)-xcex1-(2-Methylethyl)-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1).
(xcex1R)-xcex1-(2-Methylethyl)-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xc2x1)-xcex1-Butyl-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-xcex1-Butyl-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 2).
xc2x1)-xcex1-Octyl-2-oxo-2-(4-phenoxyphenyl)- 1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 1).
(xc2x1)-xcex1-Octyl-2-oxo-2-(4-phenoxyphenyl)-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid (diastereomers 2).
(xc2x1)-2-Oxo-2-(2-phenylethyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Methoxyphenyl)-2-oxo-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-phenyl-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid.
(xc2x1)-2-Heptyl-2-oxo-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid (compound 159).
(xcex1R)-2-(4-Biphenylyl)-xcex1-(1-methylethyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xc2x1)-2-[4-(4-Chlorophenyloxy)-phenyl]-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-[4-(4-Chlorophenyloxy)-phenyl]-2-oxo-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid.
(xcex1R)-2-[4-(4-Chlorophenyloxy)-phenyl]-xcex1-(2-methylethyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4xe2x80x2-Bromo-4-biphenylyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4xe2x80x2-Bromo-4-biphenylyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-(4xe2x80x2-Bromo-4-biphenylyl)-2-oxo-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid.
(xc2x1)- 2-[2-(1-Naphtyl)-ethyl]-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-Phenyl-2-thioxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-Phenyl-2-thioxo-1,3,2-oxazaphosphorepane-3-acetamide.
(xc2x1)-2-Phenyl-2-thioxo-1,3,2-oxazaphosphorocane-3-acetamide.
(xc2x1)-2-[4-(4-Chlorophenyloxy)-phenyl]-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Bromophenyl)-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-(4-Bromophenyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-(4-phenylmethoxyphenyl)-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-(4-phenylmethoxyphenyl)-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-(4-phenylmethoxyphenyl)-1,3,2-oxazaphosphorocane-3-acetohydroxamic acid.
(xc2x1)-2-[2-(4-Chlorophenoxy)-phenyl ]-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid
(xc2x1)-2-Oxo-2-[4-(4-trifluoromethylphenoxy)-phenyl]-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-Oxo-2-[4-(4-trifluoromethylphenoxy)-phenyl]-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xcex1R)-xcex1-(2-Methylethyl)-2-oxo-2-[4-(4-trifluoromethylphenoxy)-phenyl]-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 1,).
(xcex1R)-xcex1-(2-Methylethyl)-2-oxo-2-[4-(4-trifluoromethylphenoxy)-phenyl]-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid (diastereomer 2).
(xc2x1)-2-[4-(4-Bromophenoxy)-phenyl]-2-oxo-1,3,2-oxazaphosphorinane-3-acetohydroxamic acid.
(xc2x1)-2-[4-(4-Bromophenoxy)-phenyl]-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-(4-nitrophenyl)-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid
(xc2x1)-2-[N-(4-Chlorobenzoyl)-4-aminophenyl]-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid.
(xc2x1)-2-(N-Benzoyl-4-aminophenyl-2-oxo-1,3,2-oxazaphosphorepane-3-acetohydroxamic acid;
and the corresponding carboxylic acids.
The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesised using the methods outlined below, together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
The novel compounds of formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognised by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all compounds of formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods can be used.
Compounds according to the present invention in which X is a hydroxamic acid group xe2x80x94CONHOH may be prepared from compounds of the invention in which X is a carboxylic acid group xe2x80x94COOH. That process comprises reacting an acid of general formula (II) (in these and the following formulae R1, R2, Y and n have the above meanings unless otherwise specifically indicated; R13 represents an alkyl; R14 represents an alkyl or a silyl). 
with hydroxylamine, O-protected hydroxylamine, N,O-diprotected hydroxylamine. Other substituents of the acids (II) may themselves be protected from such reaction, then removing any protecting groups from the resulting hydroxamic acid moiety and from any protected substituents in R1, and R2.
The condensation is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis, e.g. the mixed carbonic anhydride (isobutyl chloroformate) method.
Compounds according to the present invention in which X is a hydroxamic acid group xe2x80x94CONHOH may also be prepared from esters of general formula (III). That process comprises reacting an ester of general formula (III) with hydroxylamine or O-protected hydroxylamine in the presence of a base. 
Compounds according to the present invention in which X is a carboxylic acid group xe2x80x94COOH may be prepared from esters of general formula (III) by basic hydrolysis. 
The esters of formula (III) may be prepared from phosphonyl dichlorides (IV) and amino alcohols (V) in the presence of a base. 
The esters of formula (III) may also be prepared from phosphonyl dichlorides (IV) and amino alcohols (VI) in the presence of a base and subsequent alkylation of the intermediate oxazaphosphacycloalkane (VII) utilising haloesters (VIII) in the presence of a base. 
Starting materials (IV), (V), (VI) and (VIII) are either known compounds or prepared by known routine synthetic methods.
Compounds containing a phosphonic acid as a zinc-binding group (X) may be prepared by alkylation of oxazaphosphacycloalkanes (VII) with alkyl or silyl phosphonate halides (IX), in the presence of base, followed by deprotection. The deprotection of alkyl phosphonates is carried out by treatment with TMSI. Silyl phosphonates are readily converted to phosphonic acids by treatment with water. 
Compounds containing an acetylthiomethyl moiety (XII) as a zinc binding group may be prepared by alkylation of oxazaphosphacycloalkanes (VII) with an acetylthioethyl halide (XI) in the presence of base. Compounds with a mercaptomethyl zinc-binding group (XIII) may prepared by removal of the acetyl group from compound (XII) with aqueous base. 
The present compounds are intended for use in pharmaceutical compositions which are useful in the treatment of the above mentioned diseases.
The amount required of a compound of formula I (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. A suitable dose of a compound of formula I for systemic treatment is 0.1 to 200 mg/kg body weight, the most preferred dosage being 0.2 to 50 mg/kg of mammal body weight, administered one or more times daily.
While it is possible for an active ingredient, such as a compound according to this invention, to be administered alone as the raw chemical, it is preferable to administer a compound of the invention as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 0.1% to 100% by weight of the formulation. Conveniently, dosage units of a formulation contain between 0.07 mg and 1 g of the active ingredient, preferably from about 0.5 mg to about 500 mg of the active ingredient, more preferably about 50 mg, e.g. for oral administration. For topical administration, the active ingredient preferably comprises from 1% to 20% by weight of the formulation but the active ingredient may comprise as much as 50% w/w. Formulations suitable for nasal or buccal administration may comprise 0.1% to 20% w/w for example about 2% w/w of active ingredient.
By the term xe2x80x9cdosage unitxe2x80x9d is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
The formulations, both for veterinary and human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular, topical, nasal, or buccal administration.
The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste.
Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra articular and ophthalmic administration.
Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomisers. In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients.
The compositions may further contain other therapeutically active compounds usually applied in the treatment.
The invention is further illustrated by the following general procedures, preparations and examples.